In the early 1980's during the course of studies on the immune response to viral infections, scientists in LOM discovered a new type of antibody (Ab), which in contrast to classic monoreactive Ab, reacted with a variety of different antigens (Ag). They refereed to these naturally occurring Abs as "polyreactive Abs". Over the years, LOM scientists have carried out detailed studies on the properties of polyreactive Abs. They showed that polyreactive Abs are naturally occurring Abs, primarily of the IgM, but also of the IgG and IgA isotypes. These Abs are capable of reacting with a variety of Ags, both exogenous and endogenous, which may differ greatly one from another. The production of polyreactive Abs is independent of Ag immunization and the B cells capable of making polyreactive Abs often, but not always, express CD5, a pan-T cell surface marker. The affinity of polyreactive Abs is relatively low compared to the high affinity of monoreactive Abs elicited by antigen-driven maturation. In the serum, polyreactive Abs are usually present in low titer as a result of being masked by binding to endogenous Ags. Cloning and sequencing have shown that the variable region of polyreactive Abs utilize gene segments often in unmutated configuration, similar to that observed in cells of the early B cell repertoire. The biological functions of polyreactive Abs and polyreactive Ab- producing B cells are still unclear. Initially, it was thought that polyreactive Abs might constitute a first line of defense against invading microorganisms, but studies in our Laboratory now offer what may be a better hypothesis. Recently, we found that B cells capable of making polyreactive Abs have Ig receptors on their surface and can bind many different Ags. We refer to these polyreactive Ag-binding B cells as PAB cells. Characterization of these cells showed that they were IgD positive and B-7 negative. Moreover, the binding of Ags to B7 negative PAB cells did not upregulate the expression of B7. These and a number of other studies argue that PAB cells have properties that are consistent with cells that induce immunological tolerance. This hypothesis, that PAB cells may be concerned with the inactivation of T cells and the development and maintenance of immunological tolerance, is now under investigation. If this hypothesis turns out to be correct, then the role of what has been referred to as "natural Abs" may have to be reevaluated. Studies are now under way using site directed mutagenesis and other techniques to determine the structure/function relationship of polyreactive Ab molecules.